Decreased Frequency of Circulating CD34+ Hematopoietic Stem/Progenitor Cells in Preterm Infants with Late-Onset Systemic Bacterial Infection

Background:In postnatal life, hematopoietic stem/progenitor cells (HSC) mostly reside in specialized bone marrow niches, however a low number of HSC is constantly released into the peripheral circulation. Emerging evidence suggests that these circulating HSC may play an active role in the host defense mechanism against bacterial infection by fostering the local production of tissue-resident innate immune cells. In adult patients with sepsis, CD34+ cells were significantly elevated in their circulation, which correlated with monocyte production and survival. Due to the immaturity of the immune system, preterm infants are vulnerable to life-threatening systemic infection. Although neonatal blood contains relatively high levels of CD34+ cells, there has been no knowledge on whether the same regulation of circulating CD34+ cells occurs in preterm infants in response to systemic infection, as in adults.

Methods: We collected peripheral blood from preterm, very low birth weight (<1500 g) infants with suspected late-onset (>72 hours of age) infection requiring full sepsis evaluation and antibiotic treatment. Circulating CD34+ cells were assessed using 3-color flow cytometry (CD34, CD45 and 7-AAD), and enumerated using the ISHAGE gating strategy.

Results: Of 39 episodes of suspected clinical sepsis investigated, 12 were blood culture-confirmed sepsis and 27 were non-infected episodes. There were no significant differences between infected and non-infected infants in gestational age, birth weight, postnatal age at the time of sepsis screening, Apgar scores at 1 and 5 minutes, male/female ratio or white cell count. However, there was a significant decrease in the frequency of CD34+ cells (percentage of total CD45+ cells) in infected infants [median (interquartile range), 0.08 (0.06-0.16) %], when compared to non-infected episodes [0.19 (0.12-0.34) %, P = 0.001]. Concomitant increase in the frequency of neutrophils [69 (59-75) % vs. 45 (34-53) %, P < 0.001] and decrease in lymphocytes [18 (13-22) vs. 32 (27-41) %, P < 0.001] were observed during these infection episodes. In addition, an inverse correlation was found between the frequencies of CD34+ cells and neutrophils (r = -0.471, P = 0.004), whereas a positive correlation was observed between the frequencies of CD34+ cells and lymphocytes (r = 0.485, P = 0.003). Interestingly, a rebound of CD34+ cells was evidenced at 24 hours after the commencement of antibiotic treatment in the sepsis group [0.12 (0.07-0.20) %, P = 0.012] but not in the non-infected group [0.21 (0.16-0.27) %, P= 0.847], suggesting that the level of circulating CD34+ cells may be under active control and correlate with clinical progress.

Conclusions: This is the first evaluation of circulating CD34+ cells in preterm infants during an episode of systemic infection. Our data revealed a drop in the frequency of CD34+ cells in these infants at the onset of sepsis, which may be linked to the preferential commitment to neutrophilic lineage at the expense of lymphocyte production. Moreover, there is an opposite direction in the regulation of CD34+ cells in preterm infants when compared with adults affected by sepsis or other inflammatory conditions. This phenomenon may be attributed by defective mobilization, lower plasma levels of stem cell-mobilizing cytokines or insufficient stem cell pool in the bone marrow, which warrants further investigation.